Atherothrombotic vascular disease is the leading cause of sudden death and disability worldwide. Though lipid-lowering strategies have significantly reduced cardiovascular morbidity and mortality, the residual risk for cardiovascular events remains high. This necessitates the development of alterative and complementary strategies towards slowing progression of atherosclerotic disease. According to recent findings in experimental animals and humans, a major feature of advanced, rupture-prone atherosclerotic plaque is defective clearance of apoptotic cells. Apoptotic cell death, in the absence of efficient phagocyte clearance (efFerocytosis), promotes post-apoptotic necrosis, which contributes to inflammation and plaque disruption. Surprisingly, though numerous candidates have been implicated, the key factors that lead to defective efFerocytosis in-vivo have yet to be elucidated. We have recently discovered that deficiency of the cell surface receptor Mertk, reduces efferocytosls in murine lesions and promotes key features of plaque vulnerability, namely necrotic core expansion. Interestingly, preliminary data also suggest that advanced coronary disease in humans coincides with proteolytic degradation of Mertk. To determine if Mertk proteolysis contributes to plaque destabilization, we will engineer a mouse to expresses cleavage-resistant Mertk and subsequently measure plaque necrosis. In-vitro, Mertk proteolysis is driven by inflammation. In-vivo, an "inflammatory" Ly6C-hi monocyte subset is recruited to atherosclerotic lesions and differentiates into macrophage phagocytes. In collaborative work, we have found that Ly6C-hi monocytes differentiate into a subset of phagocytes with poor in-vitro efferocytosls efficiency. We hypothesize that plaque vulnerability is promoted by inflammatory phagocyte subsets with reduced functional Mertk and poor efferocytosls efficiency. We will elucidate the molecular mechanisms that regulate efferocytosis efficiency of phagocyte subpopulations both in vitro and in vivo. This overall concept presents an opportunity for novel therapeutic strategies directed against progression of inflammation and atherothrombosis, namely through the elucidation of mechanisms that control in-vivo efferocytosls efficiency and modalities aimed at restoration and augmentation of defective efferocytosls. RELEVANCE (See instructions): The study of in-vivo regulation of efferocytosls, although still at a very early stage of development, may provide the basis for therapy in numerous chronic inflammatory disorders. These studies have the potential to elucidate novel therapeutic targets that can be directed against both the accumulation of inflammatory apoptotic cells and the progression of advanced plaques, namely, through restoration and enhancement of defective effemnvtoRls.